Modified phosphocalcic compound, injectable composition containing same

ABSTRACT

The invention concerns a phosphocalcic compound modified by a gem-bisphosphonic acid or one of its salts, a method for preparing same, as well as its use for preparing an injectable composition. The modified phosphocalcic compound is obtained by adding a gem-bisphosphonic acid or one of its alkali metal or alkaline earth salts to a suspension of a precursor phosphocalcic compound in ultra-pure water, while stirring the reaction medium at room temperature, then in recovering by centrifuging the formed compound. Said compound is useful for making an injectable composition, for use in the treatment of bone remodeling equilibrium.

This is application is a 371 of PCT/FR03/00527 filed on Feb. 18, 2003.

The invention relates to a phosphocalcic compound modified with agem-biphosphonic compound, to a process for preparing it and to its usefor producing an injectable composition.

Deregulation of the bone activity of an individual is the cause of manybone pathologies such as osteoporosis, Paget's disease or osteolytictumors. Taking into account, in particular, the increase in human lifeexpectancy, osteoporosis has become a public health problem and muchresearch has been undertaken to remedy it. Since the bone pathologiesunder consideration are caused by an imbalance in bone remodeling to thebenefit of the activity of the osteoclasts, one of the routes oftreatment envisioned consisted in reducing the activity of theosteoclasts, in order to slow down the degradation of the bone material.

Studies performed on various gem-biphosphonic acids have shown theirinhibitory power on osteoclast activity (G. A. Rodan et al., TherapeuticApproaches to Bone Diseases, 1 Sep. 2000, Vol. 289, Science, pp.1508-1514). The use of some of them as medicaments, especiallyetidronate, clodronate, pamidronate, alendronate, risedronate,tiludronate and ibandronate, has been accepted in various countries.Data have been published for other gem-biphosphonic acid compounds,especially zoledronate, incadronate, olpadronate and neridronate. Thegem-biphosphonic acids that are used at the present time for thetreatment of bone lesions are used systemically and, as a result, giverise to a few undesirable side effects. They can cause renal disorderswhen they are administered intravenously, and digestivesystem-disorders, especially esophagitis or stomach ulcers, when theyare administered orally [(Lin J. H., Bone 1996; 18; 75-85) or (ThiébauldD. et al., Osteoporos Int. 1994; 76-73)]. Another drawback of the oraladministration lies in the low level of absorption of the activeprinciple onto bone material.

Injectable compositions intended to form bone substitutes are moreoverknown. FR-2 715 853 describes compositions for biomaterials forresorption/substitution of support tissues, comprising a mineral phasecomposed of BCP or calcium-titanium-phosphate, and a liquid aqueousphase comprising an aqueous solution of a cellulose-based polymer. Theseinjectable compositions contain no active principle.

Noninjectable bone substitutes, which are in the form of implants, arealso known. For example, H. Denissen et al. (J. Periodontal, Vol. 71,No. 2, February 2000, pp. 280-296) describes implants of hydroxyapatitemodified by absorption of a particular gem-biphosphonic acid, namely(3-dimethylamino-1-hydroxypropylidene)-1,1-biphosphonic acid, orolpadronate. The in situ release of the acid is said to promote bonereconstruction. However, hydroxyapatite itself has the drawback of beingvery poorly resorbable.

The aim of the present invention is to provide a composition containingan active principle that inhibits the activity of the osteoclasts andthat can be administered without producing the side effects associatedwith a systemic administration or the use of a solid implant.

Accordingly, the subject of the present invention is a modifiedphosphocalcic compound, a process for preparing it and its use as activeprinciple in an injectable composition.

The modified phosphocalcic compound according to the present inventionmay be obtained by adding a gem-bisphosphonic acid or an alkali metal oralkaline-earth metal salt thereof to a suspension of a precursorphosphocalcic compound in ultrapure water, by stirring the reactionmedium at room temperature, and then recovering the formed compound bycentrifugation. The compound may then be purified by washing withultrapure water, followed by filtering and drying in air at roomtemperature. The precursor phosphocalcic compound is chosen from calciumorthophosphates with a solubility in water of greater than 4×10⁻⁵⁹mol.l⁻¹. By way of example, mention may be made of BCPs, which are amixture of hydroxyapatite and of β-tricalcium phosphate (generallydenoted as β-TCP) in variable proportions, CDA, which is acalcium-deficient hydroxyapatite (obtained, for example, by alkalinehydrolysis of a calcium hydrogen orthophosphate), and β-TCP.

In the present text, the term “ultrapure water” means water having aresistivity in the region of 18 MΩ cm.

The stirring at room temperature is preferably maintained for a periodof between 1 hour and 72 hours, for example for 48 hours. The nature ofthe stirring and the particle size of the precursor phosphocalciccompound have an effect on the proportion of gem-biphosphonic compoundthat may be grafted. It is thus preferable, when a given particle sizehas been selected for the precursor phosphocalcic compound, to adapt thestirring so as not to modify said particle size.

The acids or salts that may be used as gem-biphosphonic compoundscorrespond to the formula (OY)(OX)P(O)—CR¹R²—P(O)(OX)(OY) in which X orY represent, independently of each other, H or an alkali metal oralkaline-earth metal cation, R¹ represents H, OH or a halogen, and R²represents:

-   -   a hydrogen or a halogen,    -   an alkyl radical,    -   an aminoalkyl radical in which the amino group optionally bears        an alkyl substituent,    -   an alkylamino radical,    -   an alkyl radical bearing an aromatic substituent comprising at        least one N atom,    -   an alkyl radical bearing an aromatic thioether group.

When R¹ and/or R² represent a halogen, Cl is particularly preferred.

When R² is an alkyl radical, alkyls containing from 1 to 6 carbon atomsare preferred.

When R² is an aminoalkyl radical, radicals NH₂(CH)_(n)— in which n isless than 6 are preferred.

When R² is an alkylaminoalkyl radical, the preferred radicals areradicals R′R″N(CH₂)_(m)— in which R′ and R″ represent, independently ofeach other, H or an alkyl radical containing up to 5 carbon atoms, and mis less than 6.

When R² is an alkylamino radical, the radicals R^(C)NH— in which R^(C)is a cycloalkyl containing from 3 to 7 carbon atoms are preferred.

When R² is an alkyl radical bearing an aromatic substituent comprisingat least one N atom, alkyls containing up to 3 carbon atoms and bearingone pyridyl or imidazolyl group are preferred.

When R² is an alkyl radical bearing an aromatic thioether group, alkylscontaining up to 3 carbon atoms and bearing a phenylthio group in whichthe phenyl group optionally bears a halogen substituent are preferred.

Among these gem-bisphosphonic compounds, mention may be made of:

-   -   etidronate (R¹=OH, R²=CH₃),    -   clodronate (R¹=Cl, R²=Cl),    -   pamidronate (R¹=OH, R²=—CH₂CH₂NH₂),    -   alendronate (R¹=OH, R²=—(CH₂)₃NH₂),    -   risedronate (R¹=OH, R²=—CH₂-3-pyridine),    -   tiludronate (R¹=H, R²=—CH₂—S—C₆H₄—Cl)    -   ibandronate (R¹=OH, R²=—CH₂—CH₂—N(CH₃)pentyl),    -   zoledronate (R¹=OH, R²=—CH₂-imidazole)    -   incadronate (R¹=H, R²=—NH-(cycloheptyl)),    -   olpadronate (R¹=OH, R²=CH₂—CH₂—N(CH₃)₂),    -   neridronate (R¹=OH, R²=—(CH₂)₅NH₂)

The acids in which R² is an alkyl radical bearing an aromaticsubstituent comprising at least one N atom, such as zoledronate orrisedronate, are particularly preferred.

A modified phosphocalcic compound according to the invention ischaracterized by the following chemical composition:

Ca_((10-a))(Mg, K, Na)_(b)(PO₄)_(6-c)(HPO₄, CO₃)_(d)(OH)_(2-e)(F, Cl,CO₃)_(f)[(OA)(OE)P(O)—CR¹R²—P(O)(OA)(OE)]_(g), in which A and Erepresent H, an alkali metal, an alkaline-earth metal or nothing, and inwhich R¹ and R² have the meaning given above, and 0<a<9; 0<b<2; 0<c<5;0<d<2; 0<e<2; 0<f<2; g<0.5. When A or E represents H, the oxygen atomthat bears it is not linked to the phosphocalcium matrix or it is simplyassociated therewith by hydrogen bonding. When A or E is “nothing”, theoxygen atom that bears it is coordinated to another element of thecomposition, for example to a Ca.

The gem-biphosphonic acid content of a modified phosphocalcic compoundmay be determined by UV-visible spectroscopy according to the methoddescribed by Ames, B. N., especially in Methods in Enzymology, Colowick,S. P. and Kaplan, N. O. Eds, Academic Press, Orlando, 1966, Vol. 8, pp.115-118. It may also be determined by liquid ³¹P NMR. Characterizationof the modified phosphocalcic compound may be performed essentially bysolid ³¹P MAS NMR, which shows both the presence of the phosphocalcicsupport and that of the active principle.

Another subject of the invention is a composition that may be used byinjection for the treatment of osteoporosis or relapses of lytic tumorsby inhibition of osteoclast activity. Said composition is a suspensionof the modified phosphocalcic compound defined above in a biocompatiblegel or solution having a viscosity that allows the transportation ofgranules of between 40μm and 500μm in size. By way of example, mentionmay be made of the hydrogels of biological interest described in Chem.Rev. (2001); 101(7): 1869-1879, especially cellulose-based hydrogels orhydrogels based on sodium hyaluronate.

The choice of the particle diameter is guided by the resorptionkinetics, on the one hand, and the injection rheology, on the otherhand. Particles less than 40μm in diameter have excessively fastbioresorption kinetics, and particles greater than 500μm in diameterhave rheology problems on injection. However, it is understood that asmall proportion of particles (up to 10% by volume) may have a diameterof less than 40μm or greater than 500μm. An injectable compositionaccording to the invention preferably contains from 40% to 75% by massof modified phosphocalcic compound, from 60% to 25% by mass of hydrogel,and optionally various additives. The additives are chosen fromcompounds capable of introducing various ions of biological interest,for instance: K⁺, Na⁺, Zn²⁺, Mg²⁺, CO₃ ²⁻, HPO₄ ²⁻, F or Cl⁻.

The composition may be prepared by suspending in a suitable medium themodified phosphocalcic compound prepared in a preliminary step. It mayalso be prepared by precipitating the modified phosphocalcic compound insitu, from a hydrogel defined as previously and precharged withphosphate ions (or calcium ions, respectively), to which will be added asuitable solution containing calcium ions (or phosphate ions,respectively) and the desired concentration of biphosphonic acid.

The mode of combination between the phosphocalcic matrix and thebiphosphonic acid differs according to the phosphocalcic matrix used,and this difference is reflected by a different biological efficacyduring in vitro tests on osteoclast cultures.

The composition according to the invention, in injectable form, allowsthe local treatment of a bone problem on the main at-risk sitesidentified (neck of the femur and body of the vertebrae), using anactive principle known for its systemic use that has various drawbacksrecalled previously. In addition, the phosphocalcic phase, which acts asa vector for the active principle, exerts an additional effect in thesense that it allows the gem-biphosphonic acid to be held in place, andit constitutes a source of calcium and of phosphate required forstimulation of the bone remodeling. Hydroxyapatite (HA), described inthe prior art as a matrix for an implant impregnated with an activeprinciple, does not form part of the phosphocalcic compounds that may beused in the present invention, since it has relatively poor solubility,it intrinsically has poor resorbability, and the introduction ofgem-biphosphonic acid reduces the resorbability potential of thephosphocalcic compounds in general.

EXAMPLES

The present invention is described in greater detail by the examplesthat follow, which are given for illustrative purposes and to which theinvention is not limited.

The following compounds and reagents were used:

-   -   ultrapure water: water with a resistivity in the region of 18 MΩ        cm    -   sodium zoledronate: gem-biphosphonic acid sold by the company        Novartis    -   sodium tiludronate: gem-biphosphonic acid sold by the company        Sanofi-Synthélabo    -   NaOH-route CDA: calcium-deficient hydroxyapatite obtained by        hydrolysis of dicalcium phosphate dihydrate with aqueous NaOH        solution (in the form of granules with a particle size of 40-80        μm)    -   ammonia-route CDA (calcium-deficient hydroxyapatite obtained by        hydrolysis of dicalcium phosphate dihydrate with aqueous        ammonia), in the form of granules with a particle size of 40-80        μm    -   β-TCP, in the form of granules with a particle size of 40-80 μm    -   BCP (75% β-TCP/25% HA) in the form of granules with a particle        size of 40-80 μm    -   BCP (25% β-TCP/75% HA) in the form of granules with a particle        size of 40-80 μm.

Example 1

Preparation of a Modified Phosphocalcic Compound

A suspension of calcium phosphate was prepared by introducing 700 mg ofBCP with a particle size of 40-80 μm into 3.5 ml of ultrapure water, and56 mg (0.14 mmol) of zoledronate were added. The suspension was placedin a tube maintained at room temperature, and was stirred with a rotarystirrer at 15 rpm for 48 hours. The suspension was then centrifuged andthe pellet was separated from the supernatant.

The solid phase was then washed several times with ultrapure water, andthen filtered off and dried at room temperature.

The process was also performed starting with the following phosphocalciccompounds: NaOH-route CDA, ammonia-route CDA and β-TCP.

Characterization of the Modified Phosphocalcic Compounds

The amount of zoledronate incorporated into each of the phosphocalcicmatrices was determined by difference, by assaying the amount ofzoledronate present in the supernatant. This assay was performed, on thesupernatant solution separated from the pellet after centrifugation, byliquid ³¹P NMR from preestablished calibration curves. It may also beperformed by UV-visible spectroscopy according to the abovementionedmethod described by Ames.

The results obtained for each of the precursor phosphocalcic compoundsare given in the table below. T (%) indicates the zoledronate content inthe final product, expressed as mg of active principle per 100 mg ofphosphocalcic compound, and P (%) indicates the percentage ofzoledronate bound to the compound relative to the amount introduced intothe reaction medium:

Precursor T (%) P (%) BCP (75% β-TCP/25% HA) 1 13 BCP (25% β-TCP/75% HA)2.7 33 NaOH-route CDA 5.2 65 Ammonia-route CDA 6.4 80 β-TCP 6.4 80

FIG. 1 represents the liquid ³¹P NMR spectrum of the supernatantobtained after centrifugation of the reaction medium corresponding tothe CDA precursor (NaOH route). The integration of the signals takesinto account the abundance of each species and the chemical shift(characteristic of the species) is given on the x-axis. Peak 1represents the zoledronate content, peak 2 represents the phosphatereleased into the medium by the phosphocalcic compound and peak 3represents the NaH₂PO₄ reference.

The liquid ³¹P NMR spectrum of the compounds obtained from the otherprecursors (except hydroxyapatite) is similar, and a release ofphosphate during reaction is noted in all cases.

The characterization of the solids obtained shows two different modes ofcombination of the zoledronate according to the nature of the startingphosphocalcic compound. FIG. 2 shows a photograph by scanning electronmicroscopy (SEM) performed on the compound obtained from β-TCP. It showsthat one form of zoledronate (probably associated with calcium)crystallizes at the surface of the phosphocalcic matrix. The samephenomenon is observed in the case of the BCPs, whether they are rich inβ-TCP (75% β-TCP−25% HA) or poor in β-TCP (25% β-TCP−75% HA).

The solid ³¹P MAS NMR data are represented in FIG. 3 for the compoundobtained from β-TCP. Spectrum 1 acquired in CP (cross-polarization) modemakes it possible to selectively observe the incorporated zoledronate.The fine signals indicate its presence in a crystalline form. Spectrum 2recorded in proton-decoupling mode makes it possible to selectivelyobserve the unchanged β-TCP support.

The solid ³¹P CP-MAS NMR spectrum is represented in FIG. 4 for thecompound derived from CDA (ammonia route). The signal for thezoledronate (peak 1) is very broad. No crystalline phase is detected atthe surface of the material, which probably indicates chemosorption ofthe zoledronate at the surface of the CDA. Peak 2 is characteristic ofCDA.

Example 2

Preparation of Phosphocalcic Compounds Modified with Tiludronate andMethylenebiphosphonic Acid

A suspension of calcium phosphate was prepared by introducing 700 mg ofβ-TCP with a particle size of 40-80 μm into 3.5 ml of ultrapure waterand 52.5 mg (0.14 mmol) of tiludronate were added. The suspension wasplaced in a tube maintained at room temperature, and was stirred with arotary stirrer at 16 rpm for 48 hours. The suspension was thencentrifuged and the pellet was separated from the supernatant.

The solid phase was then washed several times with ultrapure water, andthen filtered off and dried at room temperature.

Reactivity similar to that recorded with zoledronate is observed. FIG. 5shows the ³¹P CP-MAS spectrum of the β-TCP treated with tiludronate. Thetiludronate may be observed in the form of a crystalline phase(mulitplet 1 consisting of fine signals) deposited on the phosphocalcicphase (which appears weakly (mulitplet 2)) under these conditions inwhich the spectrum was recorded.

Example 3

Preparation of an Injectable Composition

An injectable composition was prepared from each of the modifiedcompounds obtained in examples 1 and 2, with the exception of themodified compounds obtained from hydroxyapatite, according to thefollowing process.

For each modified compound, granules were prepared, 95% by volume ofwhich granules had an equivalent particle diameter of between 40 and 80μm, and these granules were introduced into an aqueous solutioncontaining 3% hydroxypropylmethylcellulose comprising 21% by mass ofmethyl group and 8% by mass of hydroxypropyl group with a degree ofpolymerization equal to 100, so as to obtain a composition comprising49% by mass of granules.

Each of the compositions thus prepared was introduced into a glassbottle and sterilized in an autoclave at 121° C. for 20 minutes.

Example 4

In Vitro Tests of Modified Calcium Phosphates

Total bone cells, isolated from long bones of newborn rabbits, were usedto evaluate the efficacy of the combination of the modifiedphosphocalcic compound. The performance qualities of the modified BCPand of the modified ammonia-route CDA obtained in example 1 weremeasured and compared with those of the respective phosphocalcicprecursor not treated with the gem-biphosphonic acid.

For each test, two pellets of sperm whale dentine (reference compoundfor measuring the resorption) and one pellet of untreated phosphocalciccompound were placed in a first culture well, and two pellets of dentineand one pellet of surface-treated phosphocalcic compound were placed ina second culture well.

The resorption activity of the osteoclasts under these cultureconditions was evaluated (after five days) by three differentparameters:

-   1—the total number of spaces formed at the surface of the sperm    whale dentine-   2—the average surface area of the spaces-   3—the surface area of resorbed dentine.

It is seen that:

-   -   In the presence of BCP pellets modified with 1% by weight of        zoledronate, the residual resorption activity of the bone cells        of the model was undetectable. This phenomenon is thought to be        associated with a substantial release of zoledronate which had a        cytotoxic effect. Specifically, if modified β-TCP or BCP is        placed in water, a significant percentage of the zoledronate        loaded rapidly returns into solution. For example, 60 mg of        modified β-TCP suspended in 1 ml of water for 8 hours leads to        the release of about 25% of the loaded zoledronate, i.e. a molar        concentration of 10⁻² M.    -   In the presence of CDA pellets modified with 6.4% by weight of        zoledronate, the resorption activity of the cells was reduced by        about 80% relative to the zoledronate-free control. As in the        case of the modified β-TCP, if 60 mg of modified CDA are        suspended in 1 ml of water for 8 hours, no trace of zoledronate        is detected (UV-visible method). This implies that the        zoledronate is potentially present only at concentrations of        less than 10⁻⁴ M (detection limit under our analysis        conditions).

These results show that the performance qualities of the material resultnot only from the amount of zoledronate bound to the phosphocalcicmatrix, but also from the rate of release of the zoledronate, and theyconfirm a remote effect of the modified phosphocalcic matrix.

Example 5

Several samples of CDA (200 mg) modified by adding zoledronate inaccordance with the process of example 1 and several samples ofunmodified CDA were incubated in 5 ml of culture medium at 37° C. Afterincubation for 96 hours, the various supernatants were collected andused pure, diluted 10-fold, 100-fold and 1000-fold in a rabbitosteoclast model.

The results are represented in FIG. 6, in which the percentage ofresorption R is indicated on the y-axis, the conditions being indicatedon the x-axis. Among the conditions:

-   -   “vehicle” means the culture medium alone    -   “pure CDA” means the supernatant derived from the incubation of        pure CDA in the culture medium; “CDA 1/10”, “CDA 1/100” and “CDA        1/1000” mean, respectively, the solution referred to above and        diluted to 1/10, 1/100 and 1/1000    -   “pure zo” means a 10⁻⁶ M solution of zoledronate in the culture        medium, “zo 1/10”, “zo 1/100” and “zo 1/1000” mean,        respectively, the solution referred to above and diluted to        1/10, 1/100 and 1/1000    -   “pure CDAzo” means the supernatant derived from the incubation        of zoledronate-containing CDA in the culture medium, and “CDAzo        1/10”, “CDAzo 1/100” and “CDAzo 1/1000” mean, respectively, the        solution referred to above and diluted to 1/10, 1/100 and        1/1000.        These results show that:    -   the zoledronate released by the phosphocalcic phase (CDAzo)        retains its inhibitory activity on osteoclast resorption with a        pronounced dose effect,    -   CDA alone does not appear to influence the osteoclast        resorption, irrespective of the dilution of the supernatant,    -   zoledronate in solution (zo) retains its biological activity and        inhibits resorption according to a dose/effect relationship.        The comparison of the profiles of inhibition of osteoclast        resorption induced by the CDA/zo combination and by zoledronate        alone (10⁻⁶ M solution used pure, diluted 10-fold, 100-fold and        1000-fold) makes it possible to suggest that the material        releases an amount of zoledronate corresponding to a        concentration of about 10⁻⁶ M.

1. A phosphocalcic compound, having the following chemical composition: Ca_((10-a))(Mg, K, Na)_(b)(PO₄)_(6-c)(HPO₄, CO₃)_(d)(OH)_(2-e)(F, Cl, CO₃)_(f) [(OA)(OE)P(O) —CR¹R²—P(O)(OA)(OE)]_(g), in which 0<a<9; 0<b<2; 0<c<5; 0<d<2; 0<e<2; 0<f<2; g<0.5, A and E represent H, an alkali metal, an alkaline-earth metal or nothing, R¹ represents H, OH or a halogen and R² represents an element chosen from a hydrogen, a halogen, an alkyl radical, an aminoalkyl radical in which the amino group optionally bears an alkyl substituent, an alkylamino radical, an alkyl radical bearing an aromatic substituent having at least one N atom wherein the aromatic substituent is not imidazolyl or pyridyl, and an alkyl radical bearing an aromatic thioether group.
 2. The compound as claimed in claim 1, wherein R¹ and/or R² represent Cl.
 3. The compound as claimed in claim 1, wherein R² is a radical containing from 1 to 6 carbon atoms.
 4. The compound as claimed in claim 1, wherein R² is an aminoalkyl radical NH₂(CH)_(n)— in which n is less than
 6. 5. The compound as claimed in claim 1, wherein R² is an alkylaminoalkyl radical R′R″N(CH₂)_(m)— in which R′ and R″ represent, independently of each other, H or an alkyl radical containing up to 5 carbon atoms, and m is less than
 6. 6. The compound as claimed in claim 1, wherein R² is an alkylamino radical R^(c)NH— in which R^(c) is a cycloalkyl containing from 3 to 7 carbon atoms.
 7. The compound as claimed in claim 1, wherein R² is an alkyl radical containing up to 3 carbon atoms and bearing a phenylthio group in which the phenyl group optionally bears a halogen substituent.
 8. The compound as claimed in claim 1, wherein R¹ is OH, A and E represent H.
 9. A process for preparing a modified phosphocalcic compound as claimed in claim 1, comprising adding a gem-biphosphonic acid or an alkali metal or alkaline-earth metal salt thereof to a suspension of a precursor phosphocalcic compound in ultrapure water, stirring the reaction medium at room temperature and then recovering the formed compound therefrom by centrifugation.
 10. The process as claimed in claim 9, wherein the compound formed is purified by washing with ultrapure water, followed by filtering and drying in air at room temperature.
 11. The process as claimed in claim 9, wherein the precursor phosphocalcic compound is chosen from calcium orthophosphates with a solubility in water of greater than 4×10⁻⁵⁹ mol.l⁻¹.
 12. The process as claimed in claim 11, wherein the phosphocalcic compound is chosen from BCP, CDA, which is a calcium-deficient hydroxyapatite, and β-TCP.
 13. The process as claimed in claim 9, wherein the stirring at room temperature is maintained for a period of between 1 hour and 72 hours.
 14. The process as claimed in claim 9, wherein the acids or salts used as gem-biphosphonic compounds correspond to the formula (OY)(OX)P(O)—CR¹R²—P(O)(OX)(OY) in which X or Y represent, independently of each other, H or an alkali metal or alkaline-earth metal cation, R¹ represents H, OH or a halogen, and R² represents: a hydrogen or a halogen, an alkyl radical, an aminoalkyl radical in which the amino group optionally bears an alkyl substituent, an alkylamino radical, an alkyl radical bearing an aromatic substituent having at least one N atom, or an alkyl radical bearing an aromatic thioether group.
 15. A composition, comprising a suspension of the modified phosphocalcic compound as claimed in claim 1, in a biocompatible gel or solution having a viscosity that allows the transportation of granules of between 40 μm and 500 μm in size.
 16. The composition as claimed in claim 15, wherein the biocompatible gel is a hydrogel.
 17. The composition as claimed in claim 16, wherein the gel is cellulose-based hydrogen or a hydrogel based on sodium hyaluronate. 